J . Org. Chem., Vol. 42, No. 11,1977
Notes
(45) (46)
2001
(1968). W. E. Litterer, Tetrahedron Lett., 2043 (1975); (e) H. 0. House and K. A. (50) J. J. Pappas, W. P. Keaveney, E. Gancher, and M. Berger, Tetrahedron Lett., J. Snoble, J. Org. Chem., 41, 3076 (1976). 4273 (1966). Ethyl cyclopropyl acrylate undergoes addition with ( C H ~ ) ~ C U L ~ . ~ ~ ~ (51) H. Bestmann and H. Schulz, Justus Liebigs Ann. Chem., 674, 11 (1964). The syn ester 270 is stable in refluxing benzene, with or without pTsOH. (52) W. S.Wadsworth and W. D. Emmons, J. Am. Chem. Soc., 83, 1733 (1961); In the presence of ethylene glycol, a second peak (VPC) slowly appears. J. Wolinsky and K. Erlckson, J. Org. Chem., 30, 2208 (1965). Hydrolysis of the ketalization mixture provides 27e and a product which (53) The halide is commercially available (Aldrich) or can be prepared by the was identical with a material isolated from hydolysis of a ketalizationwhich method of E. A. Braude and E. A. Evans, J. Chem. SOC.,3333 (1956), folhad proceeded for an extended period of time. This substance's NMR lowed by spinning band distillation. spectrum was consistent with i, arising by an acid-catalyzed vinylcyclo(54) The enone vinyl proton in 1 and 23 appears as a triplet, while the enones propane rearrangement due to the steric compression of the ketal 18 have a multiplet resembling a doublet of doublets. group. (55) The manganese dioxide (ref 39) had been prepared several years earlier and was suitable withovt special treatment. When the reagent was activated by azeotropic removal of water (ref 56), the aldehyde was destroyed. The Collin's oxidation (ref 26a) could be used without complications. (56) I. M. Goldman, J. Org. Chem., 34, 1979 (1969). (57) The combustion analysis of this compound was consistently low in carHO bon. (58) 0. Mer, H. Gutmann, M. Montavon, R. Ruegg, G. Ryser, and P. Zeller. Helv. Chim. Acta, 40, 1242 (1957). (59) R. D. Clark and C. H. Heathcock, J. Org. Chem., 41, 1396 (1976). (60) The chromatographic properties of the two series of compounds are similar. The ketalization in the trans series gave no sign of rearrangement products It is unlikely that there are dramatic polarity differences between isomers. as did the syn series, cf. ref 46. Care has been taken to analyze adjacent TLC bands. Both cyclopropyl R. Srlnivasan and T. Roberts, "Organic Photochemical Synthesis", Vol. series experiments are reproducible and the difference in product comI, Wiiey-lnterscience, New York, N.Y., 1971. position argues against selective loss of one isomer. W. G. Dauben. G. W. Shaffer, and N. D. Vietmeyer, J. Org. Chem., 33,4060
w
(47) (48) (49)
Notes nitrile favors the equatorial nitrile 6b over the axial isomer 6a (6b/6a = 56/44). Subjection of the mixture to these conditions provides a thermodynamic mixture, the major component now becoming the minor component. Thus, the catalytic decomFrederick E. Ziegler? and Paul A. Wender2 position provides a kinetic mixture, wherein the axial nitrile 6a predominates. Sterling Chemical Laboratory, Yale University, New Haven, In order t o permit alkylation of t h e nitrile anion, it was Connecticut 06520 necessary t o perform the reaction with stoichiometric quanReceived November 15,1976 tities of methoxide and t o employ an aprotic solvent. Anhydrous lithium methoxide was prepared in situ from anhydrous Several years ago we described3 a method for converting methanol and butyllithium (hexane) or methyllithium (ether) aliphatic ketones into nitriles by t h e base-induced decomin dimethoxyethane (DME). When the diazene in the presposition of methyl dialkylcyanodiazenecarboxylates. T h e ence of an excess of methyl iodide was added dropwise a t 0 "C method permits the in situ methylation and carbomethoxyt o the base, the yellow diazene color was discharged and gas lation of the intermediate nitrile anions, thereby constituting a method for geminal substitution a t the a carbonyl ~ a r b o n . ~ evolution occurred providing from diazene 1b an 84% yield of products consisting of 1-methylcyclohexylnitrile 77%) and This Note provides the experimental details for this reaction. 1-carbomethoxycyclohexylnitrile(13%).This method of adThe diazenes lb-4b were readily prepared as outlined in dition of the methyl iodide is necessary, since, if the diazene Scheme I. Generation of hydrogen cyanide in situ (KCNis added first and then the methyl iodide, upwards of 70% of NH4CI) gave somewhat lower yields than liquid HCN, due t o the reaction mixture consists of l-carbomethoxycyclohexylwater solubility of the products. nitrile. This arises from the nitrile anion reacting with genThe decomposition of diazene l b with catalytic NaOMe in erated dimethyl carbonate or unreacted diazene. T h e conMeOH at 0 "C provided cyclohexylnitrile in 94% yield (VPC). comitant addition procedure allows the alkylation to favorably When MeOH-dl was employed, cyclohexylnitrile-dl was obcompete with the acylation. An efficient procedure for the tained. The cleavage with methoxide also undergoes a depreparation of 1-carbomethoxycyclohexylnitrilewas achieved generate methoxide exchange with t h e substrate. Evidence by adding the diazene t o the LiOCHBDME containing excess for this process was obtained by employing a two-phase system of ether and water, the yellow diazene being soluble in the dimethyl carbonate. former phase. When dilute aqueous NaOH was added slowly The in situ methylation of t h e nitrile anion from diazene t o the mixture at 0 "C, t h e aqueous phase turned yellow (di2b provided a diastereomeric mixture (5c/5d = 73/27) of azenecarboxylate salt) as gas was evolved from the same phase. methylated nitriles (63%) and a diastereomeric mixture of When gas evolution had ceased, the reaction mixture was carbomethoxylated nitriles (25%). The identity of t h e minor colorless. methylated nitrile was confirmed by synthesis from t h e Diazene 2b provided approximately an equal mixture of cisDiels-Alder adduct of tiglic acid and butadiene.4b~' A similar (5a) and trans- 2-methylcyclohexylnitrile(5b), while the 4decomposition of diazene 3b provided 1-methyl-4-terttert- butyldiazene 3b gave rise to two nitriles in a ratio of 58/42 butylcyclohexylnitrile as a mixture of diastereomers (6c/6d by VPC analysis. Rickborn and J e n ~ e have n ~ ~shown t h a t the = 76/24) in 70% yield along with 23% of carbomethoxylated equilibrium ( t-BuOK/t -BuOH) of 4-tert- butylcyclohexylproduct. House and Bare* have obtained a similar ratio (71/29)
Methyldialkylcyanodiazenecarboxylatesas
I n t e r m e d i a t e s f o r T r a n s f o r m i n g Aliphatic Ketones into Nitriles
2002 J.Org. Chem., Vol. 42, No. 11, 1977
Notes
Scheme I
CN
-I
CN
Br,/CH,Cl,
asNaHCO,
\C-N=NCO,CH, /
1
oil which was dissolved in 10 mL of methanol, cooled to 0 "C with stirring, and treated with 6 mL (-150 mmol) of liquid hydrogen cyanideg (HOOD!) at such a rate that the temperature remained below 10 "C. After 15 min a heavy, white precipitate formed, requiring the addition of 10 mL of methanol to facilitate stirring. After 30 min, the mixture was filtered and washed with methanol to afford 7.0 g of white crystalline solid. Concentration of the mother liquors provided an additional 2.5 g (97.5%). Recrystallization (methanol/pentane) provided a sample of hydrazine la: mp 135-136 "C IR (CHCl3) 36003200,2235, and 1740 cm-'; NMR (CDC13) 6 3.82 (3 H, s), 4.46 (1H, br s), and 6.82 (1H, br 9). Anal. (CgH16N302):C, H, N. Hydrazine 2a: 90% yield; mp 138 OC (methanol/pentane); IR (CHC13)3700-3250,2235, and 1735 cm-l; NMR (CDC13) 6 1.14 (3 H, d,J=6Hz),3.82(2H,s),4.62(1H,brd,J=4Hz),and6.76(1H,br d, J = 4 Hz). Anal. (C10H17N302): C, H, N. Hydrazine 3a: 90% yield; mp 132-133.5 OC (methanol/pentane); IR (CHC13) 3700-3225,2230, and 1730 cm-; NMR (CDC13)6 0.90 (9 H, s), 3.80 (3 H, s), 4.54 (1 H, br s), and 6.92 (br s). Anal. (C13H23N302): C, H, N. Hydrazine 4a: 98% yield; mp 99.5-101 "C (methanoVpentane);IR (CHC13)3700-3200,2230, and 1730 cm-'; NMR (CDC13) 6 1.50 (6 H, s), 3.80 (3 H, s), 4.46 (1H, br d, J = 4 Hz), and 6.80 (1 H, br s). Anal. (C6HllN302):C, H, N. Hydrazine l a (via in situ generation of HCN). To 0.1 mol of the carbazone of cyclohexanone (vide supra) was added a solution of 15.5 g (0.3 mol) of ammonium chloride and 16 g (0.3 mmol) of potassium cyanide in 75 mL of water and 50 mL of methanol. After stirring the mixture at room temperature for 18 h, the solution was diluted with 100 mL of water and thoroughly extracted with CH2C12. After drying, concentration, and crystallization (MeOH/pentane), hydrazine la was obtained in 60% yield. Diazene lb. To a vigorously stirred mixture of 11.7 g (0.06 mol) of hydrazine la in 100 mL of CH2C12 and 15.1 g (0.18 mol) of NaHC03 in 100 mL of HzO was added dropwise 24 mL (67 mmol) of a 2.8 M Br2/CHzC12 solution over 10 min a t room temperature. After the addition had been completed, the mixture developed a persistent orange-red color (t KI-starch). The excess bromine was discharged by the addition of small portions of solid NaZS03 to the reaction mixture. The layers were separated and the aqueous phase extracted with CH2C12 (two 50-mL portions). The combined organic fractions were washed with H20 (50 mL), dried, filtered, and concentrated. The residue was distilled to provide 11.0 g (95%)of diazene l b as a bright yellow liquid: bp 115 "C (1.3 mm); IR (CC14) 1785 cm-l; NMR (CDC13)6 3.98 (3 H, s). Anal. (CgH13N302):C, H, N. Diazene 2 b 96% yield; bp 103 "C (0.4 mm); IR (CC14) 1780 cm-'; NMR (CDCl3) 6 1.02 (3 H, d, J = 7 Hz), and 4.20 (3 H, s). Anal. (C10H15N302): C, H, N. Diazene 3 b 96% yield; mp 89.5-90.5 "C (ether/pentane); IR (CC14) 2245 and 1775 cm-'; NMR (CDC13) 6 0.96 (9 H, s) and 4.11 (3 H,
NCxxc0zCH3 CH,
H3C
t
4
3
a , X = NH-NH b, X = -N=N-
Ri
5
6
a , R, = CN; R, = H b, .R, = H; R, = CN c , 'R, = CN; R, = CH, d, :R, = CH,; R, = CN by treating 4-tert-butylcyclohexylnitrilewith lithium diethylamide followed by methyl iodide. Since methylation is among the least sterically demanding of alkylation procedures, and in view of the fact t h a t approximately 25% of carbomethoxylated product is obtained in the in situ process, it is more efficient to generate the nitriles by the protic sequence followed by alkylation using dialkylamide bases.8
Experimental Section Vapor-phase chromatography (VPC) analyses were determined on an Aerograph A-90-P or Varian Aerograph Model 90-P instrument employing a 20 ft X % in. 20% SE-30 on Chromosorb W (45/60) column. Cyclohexylnitrile, cyclohexanone, or biphenyl were used as internal standards. Infrared spectra (IR) were determined on a Perkin-Elmer Model 421 or 337 spectrometer. Nuclear magnetic resonance spectra (NMR) were recorded on a Jeolco Model JNM-MH-100 or Varian A-60A spectrometer using Me4Si as an internal standard. Melting points were determined on a FisherJohns apparatus and are corrected. Microanalyses were performed by Galbraith Laboratories or Atlantic Microlabs and are within 0.3% of the theoretical composition. Cyclohexanone, 2-methylcyclohexanone, 4-tertbutylcyclohexanone, methyl carbazate, n-butyllithium, and methyllithium were obtained commercially. Organic extracts were dried over anhydrous magnesium sulfate. Dimethoxyethane (DME) was distilled from sodium benzouhenone ketyl and methanol from Mg(OCH312. Hvdrazine l a (via liouid HCN). To a solution of 4.5 e (50.0 mmol) of methyl carbazate in i0 mL of methanol containing a &op of acetic acid was added 4.9 g (50.0 mmol) of cyclohexanone. The solution was refluxed for 30 min, concentrated in vacuo, taken up in ether, and dried. Filtration and concentration of the solution gave light yellow
SI.
Anal. (C13H21N302): C, H, N. Protic Decomposition of Diazene lb. To a solution of 540 mg (10 mmol) of NaOCH3 in 5 mL of CH30H maintained at 0 "C was added dropwise 3.9 g (20 mmol) of diazene l b in 10 mL of ether/methanol (l/l).The addition proceeded with vigorous gas evolution and required approximately 30 min for completion, during which time the temperature was maintained between 0 and 10 "C. When gas evolution had ceased, the solution was allowed to warm to room temperature and was diluted with water (10 mL). The mixture was thoroughly extracted with ether, dried, filtered, concentrated, and distilled to provide a 94% yield of cyclohexylnitrile (compared with an authentic sample). Protic Decomposition of Diazene 3b. In the manner described cis- (6a) and trans-4-tert-butylcyclohexylnitrile (6b) were obtained in 96%yield (VPC). Samples collected via preparative GLC gave: 6a, mp 57 "C (lit7b56.3-57.3 "C, IR (CC14) 2240 cm-1, NMR (CDC13) 6 0.89 (9 H, s) and 2.96 (1H, m); 6b, mp 33-34 "C (lit.7b33.4-34.7 "C), IR (Cc4) 2240 cm-', NMR (CDC13) 6 0.85 (9 H, s). Aprotic Decomposition of Diazene l a (methylation). To solution of 1.75 mL (45 mmol) of dry methanol in 20 mL of dry DME containing a trace of triphenylmethane maintained under N2 at 0 O C was added 20 mL (46 mmol) of 2.3 M BuLi in hexane until a pink color persisted. To the reaction mixture was added a solution of 1.95g (10.0 mmol) of diazene l b and 8 mL (120 mmol) of methyl iodide in 20 mL of dry DME over a period of 1 h at 3-10 OC. After the addition was complete, the reaction mixture was stirred at 25 OC for 1 h, then diluted with 40 mL of HzO and thoroughly extracted with ether, dried,
J. Org. Chem., Vol. 42, No. 11,1977 2003
Notes and concentrated. Analysis (VPC) of the residue indicated two products formed in 84%yield. The major material (86Oh) was identical (NMR, VPC collected) with 1-methylcyclohexylnitrileprepared by the procedure of House! while the minor component was identical with 1-carbomethoxycyclohexynitrile prepared from methyl 2cyano-6-heptenoate.l0 Aprotic Decomposition of Diazene 2b. In the manner described (vide supra) VPC analysis indicated an overall yield of 90% consisting of trans- 1,2-dimethylcyclohexylnitrile(5c, 46%) [IR (Ccl4) 2240 em-'; NMR (CDC13) 6 1.08 (3 H, d, J = 8 Hz), 1.34 (3 H, s), and 0.95-2.14 (9 H, m)], cis-1,2-dimethylcyclohexylnitrile(5d,17%),identical with a sample prepared from butadiene and tiglic diastereomeric 2-methyl-1-carbomethoxycyclohexylnitrile(25%)[IR (CCIJ) 2245 and 1730 cm-'; NMII. (CDC13) 6 1.04 (3 H, d, J = 6 Hz), 1.15-2.37 (4H. m), and 3.90 (3 H, s)],and diastereomeric 2-methylcyclohexylnitrile ( 1 2 %5a and 5bl, identical with material from the protic decomposition. Aprotic Decomposition of Diazene 3b. As described (vide supra). a combined yield of 95% was obtained consisting of trans-l-methyl4-tert-butylcyclohexylnitrile (53%, 6c), cis- 1-methyl-4-tert-butylcyclohexylnitrile (17%, 6d),' diastereomeric l-carbomethoxy-4tert-butylcyclohexylnitrile(23%) [IR (CC14) 2240 and 1740 em-': NMR (cc14)6 0.91 (9 H, s), 0.82-2.32 (9 H, m ) , and 3.91 ( 3 H, s)],and diastereomeric 4-tert-butylcyclohexylnitrile (_
